PROSITE documentation PDOC51537

Norovirus 3C-like protease (NV 3CLpro) domain profile

Noroviruses (NVs; formerly "Norwalk-like viruses") [E1], which belong to the Caliciviridae, are the major causative agents of nonbacterial acute gastroenteritis in humans. The NV genome, which consists of positive-sense, single-stranded RNA, contains three open reading frames (ORFs). The first ORF produces a polyprotein that is processed by the viral 3C-like protease into six nonstructural proteins. The six NV ORF1 nonstructural proteins are homologous to picornaviral nonstructural proteins and are named accordingly: N-terminal protein, 2C-like nucleoside triphosphatase, 3A-like protein, 3B VPg (genome-linked viral protein, 3C-like protease (NV 3CLpro), and a 3D RNA-dependent RNA polymerase. NV 3CLpros are the key enzymes for ORF1 polyprotein processing and also cleave the poly(A)-binding protein, causing cellular translation inhibition. NV 3CLpros belong to the chymotrypsin-like protease family, in that they appear to have chymotrypsin-like folds. Whether the 3CLpro domain has a catalytic dyad of composed of histidine and cysteine or tryad of histidine, glutamate and cysteine remains controversial [1,2]. The NV 3CLpro domain forms peptidase family C37 [E2].

The NV 3CLpro domain adopts a serine protease-like fold that consists of two β-barrels separated by a cleft within which lie the active site catalytic residues (see <PDB:1WQS>). The N-terminal β barrel has two α-helices and seven β-strands. The β-strands form a twisted antiparallel β-sheet ressembling an incomplete β-barrel. The core of the incomplete β-barrel contains hydrophobic residues. The active site histidine residue is found in the N-terminal β-barrel, as well as the glutamate. The C-terminal six-stranded antiparallel β-barrel contains the active site cysteine. The catalytic site formed is situated deep within a cleft between the N- and C-terminal β-barrels [1,2].

The profile we developed covers the entire NV 3CLpro domain.